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2010 Grants - Origlia

Role of Microglial and Neuronal RAGE in Abeta-Mediated Synaptic Dysfunction

Nicola Origlia, Ph.D.
Institute of Neuroscience of the National Research Council University of Pisa
Pisa, Italy

2010 New Investigator Research Grant

Alzheimer's disease is characterized by clump-like formations in the brain called amyloid plaques. These plaques represent the final stage of accumulation of the protein fragment beta-amyloid. However, research suggests that earlier aggregates of beta-amyloid, which contain only a few beta-amyloid molecules, may be more neurotoxic than plaques. These small accumulations are called oligomers, and they may be involved in impairing cell-to-cell communication in the brain.

Nicola Origlia, Ph.D., and colleagues plan to study how amyloid oligomers inhibit the function of synapses, the tiny channels through which brain cells communicate with one another. The researchers will focus on the entorhinal cortex, a brain region associated with memory. Using cultured brain cells and mice engineered to develop Alzheimer-like symptoms, they will test whether amyloid build-up leads to brain inflammation—and whether this inflammation plays a role in synaptic damage and cognitive loss. The investigators will then assess how beta-amyloid receptors, or "docking sites," on cells may enhance amyloid toxicity. They will focus on a docking site called receptor for advanced glycation endoproducts (RAGE). Using mice engineered to overexpress RAGE, the team will determine whether this receptor promotes amyloid-induced synaptic damage and whether it is involved in amyloid-related brain inflammation.

The results of Dr. Origlia's study could shed new light on how beta-amyloid may affect brain cell health in Alzheimer's disease. The work could also identify RAGE as a possible therapeutic target for Alzheimer treatments.